MLH1

Case Study 1: Berna Somuncu, 2022

The synthetic lethal interaction between the mismatch repair (MMR) protein, MutL homolog 1 (MLH1), and the mitochondrial base excision repair protein, DNA polymerase γ (Pol γ) was used in this study for the selective treatment of MLH1 deficient cancers. Germline mutations in the MLH1 gene and aberrant MLH1 promoter methylation result in an increased risk of developing many cancers, including nonpolyposis colorectal and endometrial cancers. Because the inhibition of Pol γ in MLH1 deficient cancer cells provides the synthetic lethal selectivity, the researchers conducted a comprehensive small molecule screening from various databases and chemical drug library molecules for novel Pol γ inhibitors that selectively kill MLH1 deficient cancer cells. CR reduced the cell proliferation of MLH1 deficient HCT116 human colon cancer cells and suppressed HCT116 xenograft tumor growth whereas it did not affect the MLH1 proficient cell proliferation and xenograft tumor growth. CR caused mitochondrial dysfunction and cell death by inhibiting Pol γ activity and oxidative mtDNA damage repair, increasing the production of reactive oxygen species and oxidative mtDNA damage in MLH1 deficient cells.

Fig1. Real-time dynamic monitoring of the cytotoxic effects of CR on HCT116V1 (MLH1 proficient).

Fig2. CR increases ROS in MLH1 deficient cells.

Case Study 2: Yuling Huang, 2022

Mut L homolog-1 (MLH1) is a key DNA mismatch repair protein which participates in the sensitivity to DNA damaging agents. However, its role in the radiosensitivity of tumor cells is less well characterized. This study investigated the role of MLH1 in cellular responses to ionizing radiation (IR) and explored the signaling molecules involved. The isogenic pair of MLH1 proficient (MLH1+) and deficient (MLH1-) human colorectal cancer HCT116 cells was exposed to IR for 24 h at the dose of 3 cGy. The clonogenic survival was examined by the colony formation assay. Cell cycle distribution was analyzed with flow cytometry. Changes in the protein level of MLH1, DNA damage marker γH2AX, and protein kinase A catalytic subunit (PRKAC), a common target for anti-tumor drugs, were examined with Western blotting. The results showed that the HCT116 (MLH1+) cells demonstrated increased radio-resistance with increased S population, decreased G2 population, a low level of γH2AX, a reduced ratio of phosphorylated PRKACαβ to total PRKAC, and an elevated level of total PRKAC and phosphorylated PRKACβII following IR compared with the HCT116 (MLH1-) cells. Importantly, silencing PRKAC in HCT116 (MLH1+) cells increased the cellular radiosensitivity.

Fig3. The human colon carcinoma cell line HCT116 deficient in the MLH1 gene was used in this study.

Fig4. The protein levels of MLH1, γH2AX, and PRKAC in the HCT116 cells before and after IR.

MLH1 involved in several pathways and played different roles in them. We selected most pathways MLH1 participated on our site, such as Mismatch repair, Fanconi anemia pathway, Pathways in cancer, which may be useful for your reference. Also, other proteins which involved in the same pathway with MLH1 were listed below. Creative BioMart supplied nearly all the proteins listed, you can search them on our site.

MLH1 has several biochemical functions, for example, ATP binding, ATPase activity, contributes_to MutSalpha complex binding. Some of the functions are cooperated with other proteins, some of the functions could acted by MLH1 itself. We selected most functions MLH1 had, and list some proteins which have the same functions with MLH1. You can find most of the proteins on our site.

MLH1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with MLH1 here. Most of them are supplied by our site. Hope this information will be useful for your research of MLH1.

PMS2; TMSB4X

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